Field of the Invention
The present invention relates to methods for the prevention and therapy of respiratory disorders, including moderate/severe chronic obstructive pulmonary disease (COPD).
Discussion of the Background
Glycopyrronium bromide (also known as glycopyrrolate) is a long acting anti-muscarinic agent (LAMA), particularly active as an antagonist on the M3 sub-type cholinergic receptors, used to reduce salivation associated with administration of certain anaesthetics, and as adjunctive therapy for peptic ulcers. It has also been reported to be effective in the treatment of asthmatic symptoms (Hansel et al., Chest, 2005; 128:1974-1979, which is incorporated herein by reference in its entirety).
WO 2005/107873, which is incorporated herein by reference in its entirety, discloses the use of glycopyrrolate for the treatment of childhood asthma.
WO 01/76575, which is incorporated herein by reference in its entirety, discloses a controlled release formulation for pulmonary delivery of glycopyrrolate. The formulation is intended for use in treatment of respiratory disease, in particular chronic obstructive pulmonary disease (COPD). The application focuses on dry powder formulations suitable for delivery by means of a dry powder inhaler (DPI).
WO 2005/074918, which is incorporated herein by reference in its entirety, discloses combinations of glycopyrrolate with glucocorticoid drugs, and their use for treating diseases of the respiratory tract.
WO 2005/110402, which is incorporated herein by reference in its entirety, discloses combinations of glycopyrrolate and a long acting beta-2 agonist (LABA) of the class of indane or of benzothiazole-2-one derivatives for treatment of inflammatory or obstructive airway diseases.
WO 2006/105401, which is incorporated herein by reference in its entirety, discloses combinations of a LAMA, an inhaled corticosteroid (ICS) and a LABA for prevention and treatment of respiratory, inflammatory or obstructive airway diseases. The anticholinergic is optionally glycopyrrolate.
According to WO 2007/057223 and WO 2007/057222, both of which are incorporated herein by reference in their entireties, disclose combinations of glycopyrronium bromide respectively with an anti-inflammatory ICS and, in particular, with mometasone furoate provide a therapeutic benefit in the treatment of inflammatory and obstructive airways diseases.
WO 2007/057221 and WO 2007/057219, both of which are incorporated herein by reference in their entireties, disclose combinations of a glycopyrronium salt with an indanyl derivative LABA (or analogue) and respectively with an anti-inflammatory steroid and, in particular, with mometasone furoate.
Formoterol is a LABA that displays a rapid onset of action and capable of relaxing smooth muscle in the bronchi and opening the airways to reduce wheezing conditions. It is commonly used in the management of asthma and other respiratory conditions.
An effective combination therapy comprising formoterol fumarate and the ICS beclometasone dipropionate (BDP) has become available under the trade-name Foster®. Foster® is designed for delivery by aerosol to the lungs using a pressurized metered dose inhaler (pMDI). It has long been known that aerosol solutions of formoterol fumarate are relatively unstable and have a short shelf-life when stored under suboptimal conditions. The Foster® formulation incorporates a suitable amount of inorganic acid in order to stabilize the formoterol component (as described in EP 1 157 689, which is incorporated herein by reference in its entirety).
Dry powder inhalation (DPI) formulations of glycopyrronium bromide alone or in combination with the LABA indacaterol maleate have been approved and in the market for some years in the long term, maintenance treatment of airflow obstruction in patients with COPD. More recently also a pMDI co-suspension formulation of glycopyrronium bromide (10.4 μg per actuation) solid particles and formoterol fumarate (4.8 μg per actuation) solid particles with porous particles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride has been approved in the same indication.
US 2011/0150782, which is incorporated herein by reference in its entirety, discloses a stable pMDI solution formulation of a combination of glycopyrronium bromide, formoterol or a salt thereof, and beclometasone diproprionate (BDP).
US 2015/0182450 and US 2015/0182459, both of which are incorporated herein by reference in their entireties, disclose a pMDI solution formulation of a combination of glycopyrronium bromide, formoterol or a salt thereof, and BDP wherein the level of a specific degradation product, from the interaction between formoterol and glycopyrronium bromide is minimized after storage in particular container closure systems.
However, it would be desirable to provide a clinically useful aerosol product that combining in a single inhaler the therapeutic benefits of the bronchodilators formoterol and glycopyrronium bromide with the anti-inflammatory effect of beclometasone dipropionate is particularly effective for the treatment of moderate/severe COPD, especially in reducing the level of exacerbations in patients which were in therapy with a double inhalation therapy comprising ICS+LABA, ICS+LAMA and LABA+LAMA or with a single LAMA by inhalation which have experienced more than one exacerbation within the last year.
An exacerbation of COPD, as defined in Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guideline (2015) is an acute event characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.